Monoclonal antibodies that bind to HGM-CSF and medical compositions comprising same
Inventors
Takada, Kenzo • Nakajima, Kantou • Kistler, Barbara • Park, John
Assignees
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Publication Number
US-8679502-B2
Publication Date
2014-03-25
Expiration Date
Abstract
Disclosed herein are anti-hGM-CSF monoclonal antibodies and antigen-binding fragments of such antibodies, with improved neutralizing capacity to hGM-CSF activity. Pharmaceutical compositions comprising such an antibody or antigen-binding fragment are also provided. The present invention is useful for the treatment of various diseases that are associated with aberrant expression of hGM-CSF.
Core Innovation
The invention relates to isolated anti-hGM-CSF monoclonal antibodies or antigen-binding fragments that bind and neutralize hGM-CSF through a discontinuous hGM-CSF epitope. The antibodies are defined by specific heavy-chain and light-chain CDR amino-acid sequences, including V_H-CDR1 SYGMH (SEQ ID NO: 4), V_H-CDR2 LTYHHGNRKFYADSVRG (SEQ ID NO: 5), V_H-CDR3 ESMGAINDN (SEQ ID NO: 6), V_L-CDR1 IGNNNNIGSHAVG (SEQ ID NO: 7), V_L-CDR2 GRSPPS (SEQ ID NO: 8), and V_L-CDR3 STWDSSLSAVV (SEQ ID NO: 9). Exemplary antibody embodiments include EV1018 and EV1019 and their fragments, with sequence-defined antibody binding features.
The disclosure further provides embodiments specifying complete heavy-chain variable region and light-chain variable region sequences, including SEQ ID NO: 348 and SEQ ID NO: 365, SEQ ID NO: 361 and SEQ ID NO: 365, and related heavy-chain and light-chain sequence identifiers such as SEQ ID NO: 46 with SEQ ID NO: 36, and SEQ ID NO: 51 with SEQ ID NO: 36. The scope includes full-length antibodies, recombinant forms, antigen-binding fragments such as Fab and scFv, and related sequence-defined constructs.
The document also includes isolated nucleic acids and vectors encoding the heavy and light chain CDR-containing components, as well as compositions comprising the isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment. It further addresses neutralizing activity and binding relationships, reporting that neutralization potency is unexpectedly not linearly correlated with binding affinity, and provides associated host cells, pharmaceutical compositions, and kits for therapeutic use.
Claims Coverage
The consolidated claim set covers six core inventive feature groups, with additional sequence- and format-specific claims. The independent claims are directed to sequence-defined isolated anti-hGM-CSF monoclonal antibodies or antigen-binding fragments, specified variable-region or full-chain sequence pairs, DNA vectors encoding the specified heavy or light chains, and compositions comprising the sequence-defined antibody.
CDR-defined isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment
An isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain with V_H-CDR1 SYGMH (SEQ ID NO: 4), V_H-CDR2 LTYHHGNRKFYADSVRG (SEQ ID NO: 5), V_H-CDR3 ESMGAINDN (SEQ ID NO: 6), and a light chain with V_L-CDR1 IGNNNNIGSHAVG (SEQ ID NO: 7), V_L-CDR2 GRSPPS (SEQ ID NO: 8), and V_L-CDR3 STWDSSLSAVV (SEQ ID NO: 9).
Variable-region sequence defined isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment
An isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain variable region sequence of SEQ ID NO: 348 and a light chain variable region sequence of SEQ ID NO: 365, or a heavy chain variable region sequence of SEQ ID NO: 361 and a light chain variable region sequence of SEQ ID NO: 365.
Sequence defined isolated anti-hGM-CSF monoclonal antibody
An isolated anti-hGM-CSF monoclonal antibody comprising a heavy chain sequence of SEQ ID NO: 46 and a light chain sequence of SEQ ID NO: 36, or a heavy chain sequence of SEQ ID NO: 51 and a light chain sequence of SEQ ID NO: 36.
DNA vector encoding CDR-defined anti-hGM-CSF antibody heavy or light chain
A vector comprising a DNA sequence encoding a heavy chain or a light chain of an anti-hGM-CSF antibody comprising the specified VH-CDR or VL-CDR sequences.
Composition comprising CDR-defined isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment
A composition comprising an isolated anti-hGM-CSF monoclonal antibody or antigen-binding fragment thereof comprising the specified heavy-chain and light-chain CDR sequences.
Overall, the claims anchor the invention around isolated anti-hGM-CSF monoclonal antibodies and antigen-binding fragments defined by fixed heavy-chain and light-chain sequence identities, together with corresponding DNA vectors and compositions containing the sequence-defined antibody.
Stated Advantages
Highly increased neutralizing potency of anti-hGM-CSF antibody combinations in TF-1 proliferation assays.
Functional neutralization of hGM-CSF activity, including IC50 and near-complete inhibition at low concentrations for specific antibody mixtures.
Inhibition of U937 IL-8 secretion.
Inhibition of CD11b/Mac1 induction on primary granulocytes.
In vivo reduction of cigarette smoke-induced pulmonary inflammation and inflammatory cytokines after anti-GM-CSF antibody pretreatment.
Neutralization potency is unexpectedly not linearly correlated with binding affinity.
Fully human antibodies are described in the disclosure, with a low-immunogenicity rationale stated.
Documented Applications
Neutralization of hGM-CSF activity assessed in TF-1 proliferation assays.
Inhibition of U937 IL-8 secretion.
Inhibition of CD11b/Mac1 induction on primary granulocytes.
In vivo treatment/pretreatment context using a cigarette smoke model in mice to reduce pulmonary inflammation and inflammatory cytokines.
Epitope mapping of antibody epitopes on GM-CSF, including conformational/non-linear and discontinuous epitope regions distinct from EV1003.
Treating hGM-CSF-overexpression diseases including allergic, autoimmune, respiratory, and leukemia indications.
Treating diseases including asthma, COPD, rheumatoid arthritis, psoriasis, myeloid leukemia, and multiple sclerosis.
Combination use to enhance inhibitory effects.
Therapeutic use through associated pharmaceutical compositions and kits.
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